Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[C:12]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[C:11]2[CH2:25][CH2:26][C:27]([OH:29])=O>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[C:12]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[CH:11]2.[CH3:25][CH2:26][C:27]([Cl:4])=[O:29]
Reactant: Cn1c(-c2ccc(Cl)cc2)c(CCC(=O)O)c2cc(Cl)ccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCC(=O)Cl
Product: Cn1c(-c2ccc(Cl)cc2)cc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (0.08 mL, 114 mg, 0.9 mmol) was added dropwise to a stirred, cooled (0° C.) solution of 5-chloro-2-(4-chlorophenyl)-1-methyl-1H-indole-3-propanoic acid (Description 12, 330 mg, 0.95 mmol) and DMF (1 drop) in toluene (15 mL) and the mixture was stirred at room temperature for 2 h. to give a solution of 5-chloro-2-(4-chlorophenyl)-1-methyl-1H-indole-3-propanoyl chloride. Sodium hydride (60% dispersion in mineral oil, 19 mg, 0.48 mmol) was added to a solution of phenylmethyl 3-oxo-1-piperazinecarboxylate (Eur.J.Med.Chem. 1981, 16, 229-232) (111 mg, 0.48 mmol) in DMF (3 mL) and the mixture was stirred at room temperature for 30 min. A portion of the solution of 5-chloro-2-(4-chlorophenyl)-1-methyl-1H-indole-3-propanoyl chloride (7.5 mL) was added dropwise and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ether. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (80:20). The fractions containing product were combined, washed with aqueous sodium hydroxide (4M) and water, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane and washed with aqueous hydrochloric acid (2M), saturated aqueous sodium carbonate and water, dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless oil (14 mg, 5%). δ7.58 (1H, s), 7.47 (2H, d, J 8.4 Hz), 7.39-7.16 (9H, m), 5.15 (2H, s), 4.22 (2H, s), 3.81 (2H, m), 3.61 (2H, m), 3.53 (3H, s), 3.15 (2H, m), and 3.00 (2H, m). m/z (ES+) 564, 566 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36]C(C)(C)C)=O)[CH2:30][CH2:29]2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:24])[NH:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:11][C:10]=2[N+:25]([O-:27])=[O:26])=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.CC1C(N2CCNCC2)=NC([NH:55][C:56]2[CH:71]=[CH:70][C:59]([C:60]([NH:62]C3CCN(C)CC3)=O)=[CH:58][C:57]=2[N+]([O-])=O)=NC=1.N(C1C=CC(C#N)=CC=1)=C=O.C(N(CC)CC)C>C(Cl)Cl>[C:60]([C:59]1[CH:70]=[CH:71][C:56]([NH:55][C:34]([N:31]2[CH2:32][CH2:33][N:28]([C:3]3[C:2]([CH3:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]4[CH:14]=[CH:13][C:12]([C:15](=[O:24])[NH:16][CH:17]5[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]5)=[CH:11][C:10]=4[N+:25]([O-:27])=[O:26])[N:4]=3)[CH2:29][CH2:30]2)=[O:36])=[CH:57][CH:58]=1)#[N:62]
Reactant: Cc1cnc(Nc2ccc(C(=O)NC3CCN(C)CC3)cc2[N+](=O)[O-])nc1N1CCNCC1
Reactant: Cc1cnc(Nc2ccc(C(=O)NC3CCN(C)CC3)cc2[N+](=O)[O-])nc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: N#Cc1ccc(N=C=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(Nc2ccc(C(=O)NC3CCN(C)CC3)cc2[N+](=O)[O-])nc1N1CCN(C(=O)Nc2ccc(C#N)cc2)CC1
Reaction time: 1 h
Yield: 222 %

Procedure:
To a solution of tert-butyl 4-(5-methyl-2-((4-((1-methylpiperidin-4-yl)carbamoyl)-2-nitrophenyl)amino)pyrimidin-4-yl)piperazine-1-carboxylate (0.073 g, 0.13 mmol) in DCM (1.0 mL) was added TFA (1.0 mL) and the mixture was stirred for 1 h. An aliquot of the reaction mixture was analyzed by LCMS, which indicated that the reaction had proceeded to completion. The solvents were removed and the residue was dried on high vacuum. The crude product was used for the next step without further purification. To a solution of 4-((5-methyl-4-(piperazin-1-yl)pyrimidin-2-yl)amino)-N-(1-methylpiperidin-4-yl)-3-nitrobenzamide (0.073 mmol) in DCM (1.5 mL) was added 4-isocyanatobenzonitrile (23 mg, 0.16 mmol) and triethylamine (0.055 mL, 0.39 mmol) and the mixture was stirred at 23° C. for 16 h. reaction. The crude reaction mixture was filtered and washed with minimal volume of DCM and then hexanes to give the title compound (97 mg, 100%). MS (ES+) C30H34N10O4 requires: 598. Found: 599 [M+H]+
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:22]([CH3:24])=[CH2:23])[C:6]2[O:10][C:9]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:21]=1)#[N:2].[H][H]>[Pd].O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:22]([CH3:24])[CH3:23])[C:6]2[O:10][C:9]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:21]=1)#[N:2]
Reactant: C=C(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)OC)cc3)oc12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2nc3cc(C#N)cc(C(C)C)c3o2)cc1
Yield: 99.1 %

Procedure:
To a 5-gallon reaction vessel was added methyl 4-(5-cyano-7-isopropenyl-1,3-benzoxazol-2-yl)benzoate (40.6 g, Step A), tetrahydrofuran (4 l), and 10% palladium on carbon (8 g). The reaction mixture was heated to 60° C. under 10 psi of hydrogen for 3 h, and then filtered through Celite, washing generously with dichloromethane. Concentration of the eluent in vacuo provided 40.5 g (99%) of the title compound. Mass spectrum (ESI) 321.1 (M+).
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:22]I>CN(C=O)C>[CH3:22][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:18][CH:17]=1
Reactant: CI
Reactant: Oc1ccc(C2(c3ccccc3)CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2(c3ccccc3)CCCCC2)cc1
Reaction time: 2 h

Procedure:
4-(1-phenylcyclohexyl)phenol (20 mg, 0.08 mmol) was dissolved in DMF (2 mL). A suspension of NaH in oil (60%, 5 mg, 0.125 mmol) was added. After stirring for 5 minutes methyl iodide (0.05 mL; 0.8 mmol) was added. The reaction mixture was stirred for 2 h. (tlc indicated full conversion of the starting material) then quenched with water (10 mL). Dichloromethane (10 mL) was added. The mixture was shaken and the organic phase separated off, dried (Na2SO4) and concentrated to syrup. The title product was afforded after work-up by flash-chromatography (eluent dichloromethane). Yield: 20 mg, quantitatively. LC-MS purity (UV/MS): 100/-, Rt 6.48 min. 1H NMR data were in accordance with the data written above.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][N+:13]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=2[S:15][C:14]=1SC.[C:24]([C:27]1[CH:28]=[CH:29][C:30]([NH:47][CH2:48][CH3:49])=[C:31]([N:33]=[C:34]2[N:38]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:37](=[O:46])[CH2:36][S:35]2)[CH:32]=1)(=[O:26])[CH3:25]>>[C:24]([C:27]1[CH:28]=[CH:29][C:30]([NH:47][CH2:48][CH3:49])=[C:31]([N:33]=[C:34]2[N:38]([CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:37](=[O:46])[C:36](=[C:14]3[N:13]([CH3:12])[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=4[S:15]3)[S:35]2)[CH:32]=1)(=[O:26])[CH3:25]
Reactant: CCNc1ccc(C(C)=O)cc1N=C1SCC(=O)N1Cc1ccccc1
Reactant: CSc1sc2c([n+]1C)CCCC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2SC3=C(CCCC3)N2C)C(=O)N1Cc1ccccc1

Procedure:
The title compound was prepared in a manner similar to Example 168 by condensing intermediate 3-methyl-2-methylthio-4,5,6,7-tetrahydrobenzothiazol-3-ium p-toluenesulfonate with 2-(5-acetyl-2-ethylaminophenylimino)-3-benzylthiazolidin-4-one. MS(ESI): 519 (MH+).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[C:7]([NH:10][C:11](=[O:17])[NH:12][CH2:13][C:14](O)=[O:15])(=[NH:9])[NH2:8]>C(Cl)Cl>[ClH:2].[C:7]([NH:10][C:11](=[O:17])[NH:12][CH2:13][C:14]([Cl:2])=[O:15])(=[NH:9])[NH2:8]
Reactant: N=C(N)NC(=O)NCC(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: N=C(N)NC(=O)NCC(=O)Cl
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To 1 gal. of methylene chloride under a nitrogen atmosphere is added 229.06 g. (1.1 moles) of phosphorous pentachloride, and the resulting solution cooled to 10° C. While maintaining the temperature at 10° C., 160.13 g. (1 mole) of guanylureidoacetic acid is added portionwise, and the resulting reaction mixture allowed to stir at room temperature overnight. The product is filtered, washed with dry methylene chloride and used immediately in subsequent reactions without further purification.
Reaction SMILES: Cl[C:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O-:10])=[O:9])=[C:6](C2C=CC=CC=2)[CH:5]=1)=O.[NH2:19][C:20]1[CH:25]=[C:24]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:23]([NH:37][S:38]([C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)(=[O:40])=[O:39])=[CH:22][C:21]=1[NH2:48]>C1C(Cl)=CC=C(Cl)C=1>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([C:2]2[NH:48][C:21]3[CH:22]=[C:23]([NH:37][S:38]([C:41]4[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=4)(=[O:40])=[O:39])[C:24]([NH:26][S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:28])=[O:29])=[CH:25][C:20]=3[N:19]=2)=[CH:12][CH:11]=1)([O:10][C:4]1[CH:12]=[CH:11][CH:7]=[CH:6][CH:5]=1)=[O:9]
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(N)c(N)cc2NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=C(Cl)c1ccc(C(=O)[O-])c(-c2ccccc2)c1
Solvent: Clc1ccc(Cl)cc1
Product: Cc1ccc(S(=O)(=O)Nc2cc3nc(-c4ccc(C(=O)Oc5ccccc5)cc4)[nH]c3cc2NS(=O)(=O)c2ccc(C)cc2)cc1
Yield: 76.6 %

Procedure:
To a solution containing 8.7 g (33.6mmole) of p-chlorocarbonylphenylbenzoate dissolved in 50 ml of dichlorobenzene was added 5 g (11.2 mmole) of 1,2-diamino-4,5-bis(p-toluenesulfonamido)benzene. The resulting mixture was heated to reflux under nitrogen (frothing), and was maintained at that temperature for 2 hours. The solution was then distilled to half of the original volume, and heptane was added to precipitate the yellow product. The crude product was filtered, washed with several portions of hexane, and air-dried. The material thus obtained was reprecipitated three times from THF solution using hexane. Recrystallization from methanol afforded 5.6 g (77%) of 2-[p-carbophenoxyphenyl]-5,6-bis(p-toluenesulfonamido)-benzimidazole as an amorphous yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.O>CN(C)C=O>[F:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[N:4]1[C:14](=[O:15])[C:13]2[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]1=[O:16]
Reactant: COc1ccc(N)c(F)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2C(=O)c3ccccc3C2=O)c(F)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
A suspension of 2-fluoro-4-methoxyaniline (2.22 g) and phthalic anhydride (2.33 g) in N,N-dimethylformamide (16 mL) was stirred at 120° C. for 1 hour. The reaction mixture was cooled to room temperature. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residual crystals were suspended in ethyl acetate (5 mL), and the suspension was stirred at room temperature for 10 minutes. To the suspension was added n-hexane (25 mL), and the crystals were collected by filtration. The collected crystals were dried under reduced pressure to give 3-fluoro-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)anisole (3.35 g). This material was suspended in 1,2-dichloroethane (12.4 mL). To the suspension was added chlorosulfonic acid (1.81 mL) in a dropwise manner under ice-cooling, and the mixture was heated at reflux for 1 hour. The reaction mixture was cooled to room temperature. To the reaction mixture were added thionyl chloride (4.5 mL) and N,N-dimethylformamide (0.048 mL), and the mixture was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature, and diluted with ethyl acetate. To the mixture was added water, and the organic layer was separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residual crystals were suspended in ethyl acetate (10 mL). To the suspension was added n-hexane (30 mL), and the crystals were collected by filtration. The collected crystals were washed with n-hexane, and dried under reduced pressure to give the title compound (3.6 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:19]([O:21][CH3:22])=[O:20])=[C:14](Br)[S:15][C:16]=1[Br:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[N:26]=[CH:27][C:28](B(O)O)=[N:29][CH:30]=1>C(O)C.O.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:19]([O:21][CH3:22])=[O:20])=[C:14]([C:28]2[CH:27]=[N:26][C:25]([O:24][CH3:23])=[CH:30][N:29]=2)[S:15][C:16]=1[Br:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(Br)sc(Br)c1NC(=O)OCc1ccccc1
Reactant: COc1cnc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COC(=O)c1c(-c2cnc(OC)cn2)sc(Br)c1NC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Palladium tetrakis-triphenylphosphine is added to a degassed solution of dibromide 155 and 5-methoxypyrazin-2-ylboronic acid 156 in ethanol: water:toluene (2:1:1) and sodium carbonate. The resulting mixture is heated under N2 and stirred for 1 h at 80° C. The mixture is then cooled filtered through a 0.45 μm syringe filter and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50% ethyl acetate in hexane) provides 157.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11]12([C:21](Cl)=[O:22])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:21]([C:11]23[CH2:20][CH:15]4[CH2:14][CH:13]([CH2:19][CH:17]([CH2:16]4)[CH2:18]2)[CH2:12]3)=[O:22])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(CNC(=O)C23CC4CC(CC(C4)C2)C3)cc1

Procedure:
Subject 4.0 g. (29.0 mmoles) of p-methoxy-benzylamine, 5.7 g. (29.0 mmoles) of adamantane carboxylic acid chloride and 10 ml. of triethylamine to the process of Example 11. Crystallize the residue obtained thereby from chloroform to obtain the product of this Example, m.p. 91°-94°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[NH2:26])[C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)=[O:7].C(N(CC)C(C)C)(C)C.[CH3:36][C:37]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:38]=1[C:39](Cl)=[O:40]>C(Cl)Cl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:23]=[CH:24][C:25]([NH:26][C:39](=[O:40])[C:38]4[CH:42]=[C:43]([F:46])[CH:44]=[CH:45][C:37]=4[CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Reactant: COc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1NC(=O)c1cc(F)ccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
A mixture of 0.79 g of 5-(3-methoxy-4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.40 g of N,N-diisopropylethylamine and 0.55 g of 2-methyl-5-fluorobenzoyl chloride in 25 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is washed with water and saturated NaHCO3, dried (Na2SO4) and passed through a short pad of hydrous magnesium silicate. Hexane is added at the boil to the filtrate to give 1.05 g of the desired product as a solid.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([NH:14][CH2:15][CH:16]=[CH2:17])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])C.C([CH:20]([C:24](Cl)=[O:25])[C:21](Cl)=[O:22])C.[CH2:27]([O:29]CC)[CH3:28]>>[CH2:27]([O:29][C:24]([C:20]1[C:21](=[O:22])[N:14]([CH2:15][CH:16]=[CH2:17])[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[C:4]=1[OH:5])=[O:25])[CH3:28]
Reactant: CCOCC
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: C=CCNc1nc(SC)ncc1C(=O)OCC
Product: C=CCn1c(=O)c(C(=O)OCC)c(O)c2cnc(SC)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 25.3 g. (0.1 mole) of 4-allylamino-2-methylthio-5-pyrimidine carboxylic acid ethyl ester in 400 ml. of anhydrous diethyl ether was added 7.5 g. (0.005 mole) of ethyl malonyl chloride. The mixture was stirred at room temperature for 3 hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was dissolved in 15 ml. of ethanol and this solution was added to a solution of 2.3 g. (0.1 g. atom) of sodium in 200 ml. of ethanol. The mixture was stirred at room temperature for 5 minutes and was diluted with water, acidified with glacial acetic acid and was extracted with 150 ml. of diethyl ether. The ether layer was dried over magnesium sulfate, filtered and was acidified with gaseous hydrogen chloride. The mixture was filtered and the filtrate was cooled in ice. The precipitate which formed was collected and was recrystallized from ethyl acetate to give 0.2 g. of product--m.p. 134°-136° C.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[O:19][N:18]=[C:17]([CH3:20])[CH:16]=2)=[CH:5][CH:4]=1)#[N:2].N[CH2:24][CH:25]([OH:28])[CH2:26][OH:27].CC1ON=C(CCC(O)=O)C=1>>[OH:27][CH2:26][CH:25]1[O:28][C:1]([C:3]2[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]3[O:19][N:18]=[C:17]([CH3:20])[CH:16]=3)=[CH:21][CH:22]=2)=[N:2][CH2:24]1
Reactant: NCC(O)CO
Reactant: Cc1cc(CCCCCCCOc2ccc(C#N)cc2)on1
Agent: Cc1cc(CCC(=O)O)no1
Product: Cc1cc(CCCCCCCOc2ccc(C3=NCC(CO)O3)cc2)on1
Yield: 60 %

Procedure:
5-{7-[4-(4,5-Dihydro-5-hydroxymethyl-2-oxazolyl)phenoxy]heptyl}-3-methylisoxazole [IX; R=CH3, R1, R2, R3, R4 and R5 =H, R6 =CH2OH, Y=(CH2)7, oxazole at 4-position] was prepared from the ethyl imino-ester hydrochloride of 5-[7-(4-cyanophenoxy)heptyl]-3-methylisoxazole and 3-amino-1,2-propanediol according to the procedure of Example 1, part (c), and was obtained in about 60% yield in the form of a colorless solid, m.p. 75°-76° C., when recrystallized first from isopropyl acetate and then from acetonitrile.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[N:15]([CH3:16])[CH:14]=[N:13][CH:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][C@@H:19]1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:7]([C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[C:11]2[N:15]([CH3:16])[CH:14]=[N:13][CH:12]=2)=[O:9])[C@@H:19]1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][N:27]=1
Reactant: Cc1ccc(-c2cncn2C)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1ccc(C(F)(F)F)cn1
Product: Cc1ccc(-c2cncn2C)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(1-methyl-1H-imidazol-5-yl)benzoic acid and N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 472 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1([CH3:22])[CH2:15][CH2:14][C:13]2[C:8](=[C:9]3[CH:20]4[CH2:21][CH:17]([CH2:18][CH2:19]4)[C:10]3=[C:11]([OH:16])[CH:12]=2)[O:7]1.C(N(C(C)C)CC)(C)C.[CH3:33][O:34][CH2:35]Cl>C(Cl)Cl.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1([CH3:22])[CH2:15][CH2:14][C:13]2[C:8](=[C:9]3[CH:20]4[CH2:21][CH:17]([CH2:18][CH2:19]4)[C:10]3=[C:11]([O:16][CH2:33][O:34][CH3:35])[CH:12]=2)[O:7]1
Reactant: COCCl
Reactant: COC(=O)CCC1(C)CCc2cc(O)c3c(c2O1)C1CCC3C1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCOc1cc2c(c3c1C1CCC3C1)OC(C)(CCC(=O)OC)CC2
Yield: 74.3 %

Procedure:
To a solution of 3-(6-hydroxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H-benzo[h]chromen-2-yl)-propionic acid methyl ester from Example 13 (400 mg, 1.27 mmol) and diisopropyl ethylamine (DIPEA) (0.90 ml, 5 mmol) in 4 mL of DCM was slowly added chloromethyl methyl ether (0.30 mL, 3.8 mmol) at room temperature. The reaction was left over night. After the completion of reaction shown by TLC, the mixture was poured into brine and the organic layer was separated and dried over MgSO4. After the removal of solvents the residue was purified through flash column chromatography on silica gel (25% of ethyl acetate in hexane) to afford 340 mg of 3-(6-methoxymethoxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H-benzo[h]chromen-2-yl)-propionic acid methyl ester. 1H-NMR (300 MHz, CDCl3) δ (ppm)): 6.25 (s, 1H), 4.29 (s, 1H), 3.63 (s, 3H), 2.48 (s, 1H), 3.40 (s, 1H), 2.66-2.64(m, 2H), 2.47-2.43 (m, 2H), 1.83-1.50, (m, 12H), 1.18 (s, 3H).
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:15][C@@H:14](O)[CH2:13][N:12]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:39]=[N+:40]=[N-:41].[Na+]>ClCCl.CCOC(C)=O>[N:39]([C@H:14]1[CH2:15][C@H:10]([O:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11][N:12]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13]1)=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O[C@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=N[C@H]1C[C@H](OC(=O)c2ccccc2)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of (3S,5R)-benzyl 3-(benzoyloxy)-5-hydroxypiperidine-1-carboxylate (1 eq) in 20 mL of dichloromethane was added triethyl amine (3 eq) and methanesulfonyl chloride (1.5 eq) at 0° C. The reaction mixture was allowed to stir at room temperature for 2 hours. The crude mixture was diluted with 120 mL of EtOAc, washed with sat. aq. sodium bicarbonate, brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was dissolved in 25 mL of NMP. Sodium azide (2.2 eq) was added and the resulting suspension was stirred at 80° C. overnight. The reaction mixture was diluted with 200 mL of EtOAc and 100 mL of hexanes, washed with water, brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:2) to yield (3S,5S)-benzyl 3-azido-5-(benzoyloxy)piperidine-1-carboxylate (88%). LC/MS (m/z): 381.0 (MH+). HPLC: Rt:4.41 min.
Reaction SMILES: Cl.[NH2:2][N:3]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]1[C:9]([O:11]C)=O.Cl.O1CCOCC1.[C:20](#[N:22])[CH3:21]>>[Cl:8][C:7]1[N:3]2[C:4]([C:9](=[O:11])[NH:22][C:20]([CH3:21])=[N:2]2)=[CH:5][CH:6]=1
Reactant: CC#N
Reactant: COC(=O)c1ccc(Cl)n1N
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nn2c(Cl)ccc2c(=O)[nH]1
Temperature: 82 °C
Yield: 64 %

Procedure:
A mixture of methyl 1-amino-5-chloro-1H-pyrrole-2-carboxylate hydrochloride (Example 13 A, 2.2 g, 9.8 mmol) and 4 N HCl in dioxane (6.0 mL, 24 mmol) in acetonitrile (90 mL) was placed in a sealed tube and heated at 82° C. overnight. The reaction mixture was concentrated and diluted with fresh acetonitrile (100 mL) and triethylamine (5 mL). The reaction mixture was heated at 85° C. overnight, concentrated to dryness and diluted with EtOAc to 150 mL. The EtOAc solution was washed with 1 N HCl, followed by saturated NaHCO3 solution and brine. The solution was dried over MgSO4 and concentrated to a solid. The solid was triturated with Et2O/hexane to give the title compound as a brown solid (1.15 g, 64%): 1H NMR (CDCl3) δ 6.99 (d, 1H, J=4.38 Hz), 6.42 (d, 1H, J=4.38 Hz), 2.40 (s, 3H); MS (ESI+) 183.98, 185.97 (M++H).